tbuckley/cabot-search huggingface dataset:
Abstract A012: Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation
Authors: Reetta Nätkin, Pasi Pennanen, Heimo Syvälä, Merja Bläuer, Juha Kesseli, Teuvo L.J. Tammela, Matti Nykter, Teemu J. Murtola
Journal: Cancer Research (2023)

Abstract Development of novel and efficient treatments for advanced prostate cancer (PCa) requires better understanding of the cellular mechanisms behind the transition to castration resistant prostate cancer (CRPC). We created long-term cell cultures to model the development of castration resistance. Using a low passage VCaP cells as an initial model, we first created a highly testosterone-dependent PCa cell line (VCaP-T) and then a subclone cell line developing the ability to grow at low testosterone concentration (VCaP-CT). Adaptation to low testosterone was solely due to long term culturing and experimental work confirmed for example higher AR expression and antiandrogen resistance in VCaP-CT compared to VCaP-T. With the developed models we aimed to uncover persistent and adaptive responses to testosterone level and to identify genes that potentially contribute to transition and proliferation of the castration resistant cells through androgen receptor (AR) regulation. Expression levels were measured using RNA-seq. We defined AR-associated genes as the ones with changes due to testosterone depletion in VCaP-T (418 genes) and further adaptive genes as the ones that restored expression level in VCaP-CT (134 genes). Interestingly, we identified 151 genes that were non-AR-associated in VCaP-T but gained the association in VCaP-CT cells. Genes gaining the AR-association were also hypothesized to be important for CRPC progression and castration resistant cells. We validated and assessed the clinical significance of the model and the findings using The Cancer Genome Atlas Prostate Adenocarcinoma data and multivariate Cox regression analysis. Expressions of 47 AR-associated or association gaining genes were statistically significant markers for progression-free survival. These included genes related to immune response, adhesion and transport. Genes ABCC5, SPRED3, TMPRSS11F, SPARC, SLC1A1, SATB1, PDGFRB and C1QTNF6 showed strong evidence being associated with tumor stage and aggressiveness in addition to progression-free survival. Taken together, we identified and validated multiple genes being linked with progression of prostate cancer and proposed several novel risk genes. These findings increase knowledge on mechanisms of castration resistance and may open new possibilities for treatments. Identified genes have potential to be used as biomarkers or therapeutic targets after further studies. Citation Format: Reetta Nätkin, Pasi Pennanen, Heimo Syvälä, Merja Bläuer, Juha Kesseli, Teuvo L.J. Tammela, Matti Nykter, Teemu J. Murtola. Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A012.
Abstract B068: Treatment combinations targeting MCL-1 and BCL-xL exert synergistic anti-tumor effects in AR-V7 expressing CRPC cell lines
Authors: Giulia C. Napoli, Andres F. Leon, Erica L. Beatson, Keith T. Schmidt, Emily N. Risdon, Cindy H. Chau, Douglas K. Price, William D. Figg
Journal: Cancer Research (2023)

Abstract Therapeutic agents that overcome acquired resistance to current androgen receptor (AR) pathway targeted therapies in patients with castration-resistant prostate cancer (CRPC) remain an unmet clinical need. A multitude of pathways are implicated in acquired treatment resistance, including the PI3K/mTOR/AKT, WNT/β-catenin, and DNA damage repair pathways. Notably, the androgen receptor splice variant 7 (AR-V7) activates the AR pathway in the absence of androgens, playing a crucial role in CRPC progression. An unbiased high throughput drug screen evaluating an array of inhibitors targeting diverse signaling pathways revealed highly synergistic activity of BH3 mimetics in AR-V7 expressing CRPC cell lines (e.g. LNCaP95, 22Rv1, VCaP-CR). Combinations targeting MCL-1 and BCL-xL (S63845 with A-1331852 or Navitoclax) displayed increased antitumor activity compared to those targeting MCL-1 and BCL-2 (S63845 with Venetoclax). Synergy among BCL-xL and MCL-1 targeted combinations was demonstrated using 2D and 3D CellTiter-Glo viability assays. Combination treatments in 3D spheroid cultures of 22RV1 and LNCaP95 cells confirmed the synergy observed in 2D assays. Furthermore, combined BCL-xL and MCL-1 inhibition altered AR-V7 expression and activated c-PARP cleavage. Drug combinations synergistically targeting BCL-xL and MCL-1 should be further explored for the treatment of therapy-resistant CRPC. Citation Format: Giulia C. Napoli, Andres F. Leon, Erica L. Beatson, Keith T. Schmidt, Emily N. Risdon, Cindy H. Chau, Douglas K. Price, William D. Figg. Treatment combinations targeting MCL-1 and BCL-xL exert synergistic anti-tumor effects in AR-V7 expressing CRPC cell lines [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B068.
Abstract A026: BMX inhibition reverses <i>HSD3B1</i>-driven resistance in prostate cancer
Authors: Xiuxiu Li, Michael Berk, Christopher Goins, Mohammad Alyamani, Yoon-Mi Chung, Chenyao Wang, Monaben Patel, Nityam Rathi, Ziqi Zhu, Belinda Willard, Shaun Stauffer, Eric Klein, Nima Sharifi
Journal: Cancer Research (2023)

Abstract Background: Prostate cancer is the second leading cause of cancer-related death in men in the United States and is dependent on androgens and androgen receptor (AR) activation. Androgen deprivation therapy (ADT) is the mainstay treatment, but it as well as next-generation treatments eventually fail. Disease then progresses as castration-resistant prostate cancer (CRPC), which is driven by reactivation of the androgen-AR axis. 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) catalyzes the rate-limiting step for potent androgen synthesis from adrenal-derived precursors, thereby stimulating CRPC. HSD3B1, which encodes for 3βHSD1, has a common missense-encoding germline variation that enhances conversion from adrenal DHEA to potent androgens. Clinical studies demonstrate that this “adrenal-permissive” HSD3B1 genotype confers more rapid progression on ADT, and recent studies show that overall survival is shorter in patients with the adrenal-permissive genotype who are treated with ADT + enzalutamide. The Etk/BMX kinase may be involved in the development and progression of CRPC. We sought to determine whether phosphorylation of 3βHSD1 is required for its activation and that the necessary kinase could be a potential target. Methods: In prostate cancer lines, mouse xenograft models, and fresh patient prostatectomy tissues, mass spectrometry and HPLC were used to identify steroid metabolites. Genetic and pharmacological methods were used to identify inhibition of BMX-mediated 3βHSD1 phosphorylation in CRPC. Results: BMX inhibition suppressed castration-resistant prostate cancer through targeting 3βHSD1 phosphorylation. 3βHSD1 transcription level and enzyme activity were induced in enzalutamide-resistant prostate cancer cell lines. 3βHSD1 and SF-1 transcription levels were positively correlated in prostate adenocarcinoma (TCGA database). BMX inhibition by zanubrutinib suppressed enzalutamide resistance induced 3βHSD1 enzyme activity. Conclusions: BMX promotes CRPC by regulating 3βHSD1 phosphorylation. BMX inhibition has potential as a new therapy to optimize CRPC treatment. Citation Format: Xiuxiu Li, Michael Berk, Christopher Goins, Mohammad Alyamani, Yoon-Mi Chung, Chenyao Wang, Monaben Patel, Nityam Rathi, Ziqi Zhu, Belinda Willard, Shaun Stauffer, Eric Klein, Nima Sharifi. BMX inhibition reverses HSD3B1-driven resistance in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A026.
Abstract IA012: Modeling prostate cancer metastasis in genetically engineered mouse models
Authors: Cory Abate-Shen, Arianna Giacobbe, Aleksandar Obradovic, Alessandro Vasciaveo, Florencia Picech, Kacey Ronaldson-Bouchard, Gordana Vunjak-Novakovic, Michael M. Shen, Andrea Califano, Peter Sims
Journal: Cancer Research (2023)

Abstract My laboratory has a longstanding interest in developing mouse models of prostate cancer that recapitulate the broad spectrum of prostate cancer phenotypes. We have been employing state-of-the-art systems biology approaches to integrate molecular data from our mouse models with comparable data from human prostate cancer, with the ultimate goal of informing patient care. This is exemplified by our recent description of OncoLoop, a transcriptomic framework that can support rapid-turnaround co-clinical studies to identify and validate drugs for individual patients. Our current studies have largely focused on modeling metastatic prostate cancer, particularly metastasis to bone. We have generated genetically engineered mouse models, as well as syngeneic allograft models, that model bone metastasis with high penetrance. In addition, we are employing an “organ-on-a-chip” platform that simulates bone tropism. We are using these models to decipher the molecular mechanisms that drive metastatic dissemination and bone metastasis. My presentation at this AACR conference will focus on how we have been using these various models to study circulating tumor cells (CTCs). In particular, I will describe our recent studies in which we have been using single-cell sequencing of CTCs and have generated CTC-derived organoids to interrogate mechanisms that drive dissemination and metastasis. Citation Format: Cory Abate-Shen, Arianna Giacobbe, Aleksandar Obradovic, Alessandro Vasciaveo, Florencia Picech, Kacey Ronaldson-Bouchard, Gordana Vunjak-Novakovic, Michael M. Shen, Andrea Califano, Peter Sims. Modeling prostate cancer metastasis in genetically engineered mouse models [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA012.
Abstract IA025: Pursuing novel treatment strategies for advanced prostate cancer
Authors: Johann de Bono
Journal: Cancer Research (2023)

Abstract While there have been major advances in understanding of prostate cancer biology, and outcomes including survival and quality of life for men suffering from advanced prostate cancer, the development of novel treatment strategies for aggressive prostate cancer remains an unmet medical need. Studies have shown that advanced prostate cancer has considerable inter- and intra-patient heterogeneity and biomarkers supporting disease molecular stratification are also urgently required to further improve outcomes. This presentation will focus on rational, biomarker driven, novel approaches to improve prostate cancer treatment and will discuss novel targets such as B7-H3, and the targeting of tumour-stroma paracrine interactions. Citation Format: Johann de Bono. Pursuing novel treatment strategies for advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA025.
Abstract B045: Single cell proteomics as a method to analyze circulating tumor cells in prostate cancer patients
Authors: Alec Horrmann, Zoi Sychev, Justin M. Drake
Journal: Cancer Research (2023)

Abstract The purpose of this study was to develop a single-cell proteomic protocol capable of analyzing single circulating tumor cells (CTCs). Despite the numerous benefits possible from the analysis of CTCs they have not migrated into clinical use due to difficulty of purification and their minute numbers. Combined, this results in only miniscule amounts of sample, if any, for analysis. Most clinical assays primarily focus on genomic and/or transcriptomic assays, while only a select number of proteomic assays are used and these analyze a handful of targets at most. Recent developments in single-cell proteomics using liquid chromatography tandem mass spectrometry (LC-MS/MS) promise to solve this latter issue and increase the depth of proteome coverage. To analyze CTCs we adapted previously developed single-cell methodologies to be amenable for the analysis of CTCs. Our novel method uses a separately prepared carrier channel as opposed to traditional methods which rely on a large pool of the single-cells of interest. This is necessary since collected CTC’s will not have a large pool of similar cells to draw upon to form a carrier. As the carrier is prepared in bulk it allows for improved quality control measurements to be implemented. This is critical as for clinical use these metrics will be vital for ensuring repeatability and reliability of results. Using our developed protocol, we are able to analyze hundreds of proteins from each simulated CTC. Additionally, we demonstrate that a separately prepared carrier composed of cells from a different lineage still permits the identification of a wide array of proteins within single-cells as well as allows for better quality control over the digestion and TMT labeling efficiencies. In conclusion, our protocol demonstrates its capability to detect and quantify hundreds of proteins from individual cells. If this method was applied towards the analysis of CTCs it would represent by far the most comprehensive method for analysis of the proteome of single CTCs. Together, this provides a foundation for translating proteomic analysis of single CTCs towards guiding individualized cancer treatment in the clinic. Citation Format: Alec Horrmann, Zoi Sychev, Justin M. Drake. Single cell proteomics as a method to analyze circulating tumor cells in prostate cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B045.
Abstract IA014: Drug sensitivity of multifocal primary prostate cancer
Authors: Marianna Kruithof-de Julio, Juening Kang, Sofia Karkampouna, Katja Ovchinnikova, Panagiotis Chouvardas, George N Thalmann
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is a highly heterogeneous disease with multiple and distinct cancer foci within the same prostate gland. We hypothesize that heterogeneous lesions, in terms of genomic aberrations and tumour staging, may be linked to different functional properties e.g. differential drug response sensitivity. We investigate which histopathological and molecular properties are associated with ability to maintain PCa cells as ex vivo organoid cultures and possibly specific drug responses. Interestingly, the majority of primary PCa cases showed genetic and histopathological multifocality, representing a highly heterogeneous cohort. PDOs recapitulated the genetic signature of the parental tissues. Drug responses of PDOs did not follow patient-specific patterns but rather revealed high inter- and intra-patient heterogeneity. Therapy response could be predicted based on transcriptomic profile for personalized treatment decision. The transcriptomic profile of each case was overall preserved among different cores. Drug responses in PDOs revealed not only inter- but also intra-patient heterogeneity with only 2 patient cases having positive correlation within the different cores of the same case. Statistically significant correlations were found among 8 genomic mutations and sensitivity to 5 drug compounds. Different features were tested for ML model, with RNA-seq outperforming the rest features; on average 260-1800 genes per drugs were selected for the drug prediction. ML linear regression models showed high Pearson’s correlation between predicted and observed drug response values. Citation Format: Marianna Kruithof-de Julio, Juening Kang, Sofia Karkampouna, Katja Ovchinnikova, Panagiotis Chouvardas, George N Thalmann. Drug sensitivity of multifocal primary prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA014.
Abstract A023: RNF185 modulates prostate cancer metastatic potential through regulation of epithelial-mesenchymal transition
Authors: Benjamin Van Espen, Ladan Fazli, Htoo Z. Oo, Rabi Murad, Martin Gleave, Ze'ev A. Ronai
Journal: Cancer Research (2023)

Abstract RNF185 is a RING finger domain-containing ubiquitin ligase which is anchored to the ER and resemble RNF5, a ubiquitin ligase implicated in ER associated degradation. In prostate cancer, deregulation of the expression or activity of several ubiquitin ligases has been shown to contribute to disease progression (e.g., Siah2, SPOP, RNF6). Analysis of prostate tumor patient data revealed a negative correlation between RNF185 expression and prostate adenocarcinoma progression and metastasis. Supporting these observations, several prostate cancer cell lines exhibited greater migration and invasion capabilities upon RNF185 depletion, in vitro. Subcutaneous inoculation of mouse prostate cancer MPC3 cells, stably expressing shRNA against RNF185, resulted in larger tumors and more frequent lung metastases in NSG mice. These results suggest that the increased metastatic potential associated with lower RNF185 levels may depend on molecular changes intrinsic to the tumors cells. RNA-sequencing and Ingenuity Pathway Analysis of RNF185-depleted compared to control MPC3 cells identified wound healing and cellular movement among the most significantly upregulated pathways in RNF185-depleted cells. Transcription regulators of Epithelial-Mesenchymal Transition (EMT) Snai2 and Zeb1 were among the most upregulated genes that were predicted to be activated based on the expression of their target genes. Comparison between differentially expressed genes in patients with low RNF185 expression, and RNF185-depleted cell lines (from mouse and human prostate tumors) confirmed deregulation of genes implicated in EMT. Taken together, our results identify RNF185 as gatekeeper of prostate cancer metastasis, via its control of EMT genes implicated in cell motility and metastasis. Citation Format: Benjamin Van Espen, Ladan Fazli, Htoo Z. Oo, Rabi Murad, Martin Gleave, Ze'ev A. Ronai. RNF185 modulates prostate cancer metastatic potential through regulation of epithelial-mesenchymal transition [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A023.
Abstract B057: ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer
Authors: Song Yi Bae, Hannah E. Bergom, Abderrahman Day, Joseph T. Greene, Tanya S. Freedman, Justin H. Hwang, Justin M. Drake
Journal: Cancer Research (2023)

Abstract Neuroendocrine prostate cancer (NEPC) is a lethal variant of aggressive prostate cancer. Hallmarks of NEPC include the loss of androgen receptor (AR) signaling and transdifferentiation toward small-cell neuroendocrine (SCN) phenotypes, which result in resistance to AR-targeted therapy. NEPC resembles other SCN carcinomas clinically, histologically and genomically. Here, we leveraged SCN phenotype scores of various cancer cell lines and gene depletion screens from the Cancer Dependency Map (DepMap) to identify vulnerabilities in NEPC. We discovered ZBTB7A, a transcription factor, as a candidate promoting the progression of NEPC. Cancer cells with high SCN phenotype scores showed a strong dependency with RET kinase, an emerging therapeutic target of NEPC, suggesting the NEPC-like phenotype of the cells. Then, we observed a strong correlation between dependencies of RET and ZBTB7A in these cells. Utilizing informatic modeling of whole transcriptome sequencing data from patient samples, we revealed distinct gene networking patterns of ZBTB7A in NEPC versus prostate adenocarcinoma. Specifically, we observed a robust association of ZBTB7A with genes promoting cell cycle progression in NEPC, and this result was confirmed through Gene Set Enrichment Analysis. Furthermore, we showed a potential interaction of ZBTB7A with apoptosis regulating genes. Silencing ZBTB7A in a NEPC cell line confirmed the dependency of cells on ZBTB7A for cell growth, and the role of ZBTB7A in regulating G1/S transition in cell cycle and inducing apoptosis. Collectively, our results highlight the oncogenic function of ZBTB7A in NEPC, and emphasize the value of ZBTB7A as a promising therapeutic strategy for targeting NEPC tumors. Citation Format: Song Yi Bae, Hannah E. Bergom, Abderrahman Day, Joseph T. Greene, Tanya S. Freedman, Justin H. Hwang, Justin M. Drake. ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B057.
Abstract IA002: Genomic and epigenomic regulation during prostate cancer progression
Authors: Jindan Yu
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) development and progression are controlled by aberrant expression, mutation, and function of essential transcriptional factors and epigenetic modifiers. Over the years, our work has delineated the molecular mechanisms by which androgen receptor (AR) and Polycomb Repressive Complex 2 (PRC2) protein EZH2 regulate PCa progression in concert with other key transcriptional factors such as TMPRSS2-ERG and FOXA1. We recently found that HOXB13, a homeodomain transcription factor primarily known as a pioneering factor of AR, plays an AR-independent role in inhibiting cancer metabolism and tumor metastasis. An important function that is mediated by its interaction with the HDAC3-NCoR corepressor complex, which is disrupted by the PCa risk-associated HOXB13 G84E mutation. On the other hand, we characterize the unique roles of PALI1, a newly identified PRC2-accessory protein, in mediating molecular crosstalk between PRC2 and G9A proteins to catalyze dual H3K27 and H3K9 methylation at target loci. Thus, PALI1 enforces strong repression of differentiation genes, rendering cell stemness and cancer progression. Our findings laid the foundations for the development of several new therapeutic strategies for the treatment of advanced PCa. Citation Format: Jindan Yu. Genomic and epigenomic regulation during prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA002.